Quality control pathways monitor the folding and assembly of newly synthesized secretory and membrane proteins, retaining some abnormal proteins in the endoplasmic reticulum and diverting others for degradation by cytoplasmic proteasomes. The operation of these quality control pathways underlies the cellular basis of human genetic diseases like cystic fibrosis that arise from mutations which alter the normal folding and assembly of integral membrane proteins. How the decision to degrade a misfolded or unassembled membrane protein is made, and the nature of the cellular machinery which recognizes and dislocates these proteins to cytoplasmic proteasomes for degradation is not known. Elucidating these processes is the long-term objective of the proposed research. The specific aims constitute a comprehensive approach toward these goals by addressing four questions: (1) What is the molecular basis for CFTR misfolding? (2) How do cis-degradation signals determine the fate of integral membrane proteins? (3) What is the nature of the membrane apparatus through which integral membrane proteins are dislocated from the ER? (4) What is the role of cytoplasmic factors in dislocation of integral membrane proteins from the endoplasmic reticulum?